There are now seven medications approved by the United States Food & Drug Administration (FDA) for the management of chronic hepatitis B, which fall into one of two categories: the interferons (IFNs) and the polymerase inhibitors (Lok, A. S., and B. J. McMahon. 2007. Chronic Hepatitis B. Hepatology 45:507-539). These are recommended for use in approximately 50% or less of the infected population of more than 350 million. Although this is the highest risk population, those who fall outside the treatment guidelines may also benefit from intervention, since they are also at significantly elevated risk of liver diseases. The IFNs are limited by significant side effects. The pol inhibitors target the same viral life cycle step and thus combination therapy, the bulwark of HIV and curative HCV therapy, is of limited value. They require lifelong use, and are subject to eventual use limiting toxicities, as seen with HIV long term medication use, and the emergence of drug resistant mutants. Thus, alternatives and complements to the current portfolio of medications are needed.
There is a growing belief that a “cure”, or at least sustained off-drug control of HBV, will require, or at least benefit from, drugs that control the viral nuclear genome, the covalently closed circular DNA (cccDNA). The 2006 NIDDK Liver Action Plan, reinforced by the 2010 Institute of Medicine report, all call for cccDNA inhibition as a priority for HBV drug development.
However, screening for HBV cccDNA inhibitors has been difficult, because of technical reasons: HBV cccDNA is made in amounts to low to be conveniently detected, and most viral gene products in conventionally transfected cells in culture are derived from transgenes of the viral genome, not cccDNA. The present inventors have created cell lines in which HBV gene products such as the HBeAg are produced only from cccDNA, but not from integrated viral transgene and in amounts to be robustly detected, making screening realistic (Cai, D., et al., 2012. Identification of the Disubstituted Sulfonamide Compounds as Specific Inhibitors of Hepatitis B Virus Covalently Closed Circular DNA Formation. Antimicrobial Agents and Chemotherapy: In Press; Zhou, T, et al., 2006. Hepatitis B virus e antigen production is dependent upon covalently closed circular (ccc) DNA in HepAD38 cell cultures and may serve as a cccDNA surrogate in antiviral screening assays. Antiviral Research 72:116-124).
Given such challenges, it is unsurprising that there are no HBV therapeutics in use that target HBV cccDNA and, there have been few, if any, programs to screen and develop cccDNA inhibitors. This is largely due to technical difficulties (see Block, T M, et al. 2003. Molecular viral oncology of hepatocellular carcinoma. Oncogene 22:5093-5107; Locarnini, S. 2005. Therapies for hepatitis B: where to from here? Gastroenterology 128: 789-792; Lok, A. S. 2011. Does antiviral therapy for hepatitis B and C prevent hepatocellular carcinoma? J Gastroenterol Hepatol 26:221-227). In addition, the role of host functions in regulating HBV cccDNA transcription and stability is poorly understood further frustrating development of therapeutics. Thus, any work in this area would be innovative, and would address the outstanding and long-felt need for drugs that control the viral nuclear genome of hepatitis B and otherwise provide treatment for HBV infection.